- COVALENT TARGETING OF E3 LIGASES
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Disclosed herein, inter alia, are compositions and methods for targeting E3 ligases. In an aspect is a targeted protein degrader including 1) a targeted protein binder and 2) an E3 Ubiquitin ligase binder, wherein the E3 Ubiquitin ligase is human RNF4 or human RNF114. In an aspect is provided a pharmaceutical composition including a compound as described herein, including embodiments, and a pharmaceutically acceptable excipient.
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Paragraph 0591; 0611
(2020/05/19)
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- Design and synthesis of aminothiazolyl norfloxacin analogues as potential antimicrobial agents and their biological evaluation
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A series of aminothiazolyl norfloxacin analogues as a new type of potential antimicrobial agents were synthesized and screened for their antimicrobial activities. Most of the prepared compounds exhibited excellent inhibitory efficiencies. Especially, norfloxacin analogue II-c displayed superior antimicrobial activities against K. pneumoniae and C. albicans with MIC values of 0.005 and 0.010 mM to reference drugs, respectively. This compound not only showed broad antimicrobial spectrum, rapid bactericidal efficacy and strong enzymes inhibitory potency including DNA gyrase and chitin synthase (CHS), low toxicity against mammalian cells and no obvious propensity to trigger the development of bacterial resistance, but also exerted efficient membrane permeability, and could effectively intercalate into K. pneumoniae DNA to form a steady supramolecular complex, which might block DNA replication to exhibit their powerful antimicrobial activity. Quantum chemical studies were also performed to explain the high antimicrobial activities. Molecular docking showed that compound II-c could bind with gyrase–DNA and topoisomerase IV–DNA through hydrogen bonds and π-π stacking.
- Wang, Liang-Liang,Battini, Narsaiah,Bheemanaboina, Rammohan R.Yadav,Zhang, Shao-Lin,Zhou, Cheng-He
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p. 105 - 123
(2019/02/15)
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- Design, Synthesis, and Biological Evaluation of Scutellarein Derivatives Based on Scutellarin Metabolic Mechanism in Vivo
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Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. Their thrombin inhibition activities were tested through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay and the ability to protect PC12 cells against H2O2-induced cytotoxicity, and their solubilities were evaluated by ultraviolet (UV) spectrophotometer. The results showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment. Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. The results of the biological evaluation showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment.
- Dong, Ze-Xi,Shi, Zhi-Hao,Li, Nian-Guang,Zhang, Wei,Gu, Ting,Zhang, Peng-Xuan,Wu, Wen-Yu,Tang, Yu-Ping,Fang, Fang,Xue, Xin,Li, He-Min,Cheng, Hai-Bo,Yang, Jian-Ping,Duan, Jin-Ao
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p. 946 - 957
(2016/05/24)
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- In vitro antimalarial activity, β-haematin inhibition and structure-activity relationships in a series of quinoline triazoles
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A novel series of quinoline triazole amide analogues (38-51) has been synthesized. Analogues 38-44 had a Cl substituent at the 7-position of the quinoline ring, while 45-51 had a CN substituent at this position. Compounds 40, 45 and 49 were found to be the most active in the series against the Plasmodium falciparum chloroquine-sensitive D10 strain, with IC50 values in the range of 349-1247 nM, with 40 and 45, but not 49 also exhibiting similar activity against the chloroquine-resistant K1 strain of parasite. Quinoline triazoles 40 and 44 were the most active β-haematin inhibitors, with 50% inhibitory concentrations of 14.7 and 8.9 μM respectively. In vitro antimalarial activity of the 7-Cl bearing analogues 38-44 exhibited a strong linear dependence of log(1/IC50) on log P. Thus, the more lipophilic, the more active it was found be. The 7-CN series 45-51 showed no such dependence. The resistance index (IC50 K1/IC50 D10) also exhibited a linear dependence on log P, with a substantially steeper slope in the case of the 7-Cl series. The findings demonstrate the feasibility of producing hydrophilic analogues with strong activity and low cross-resistance with chloroquine.
- Joshi, Mukesh C.,Wicht, Kathryn J.,Taylor, Dale,Hunter, Roger,Smith, Peter J.,Egan, Timothy J.
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p. 338 - 347
(2013/10/21)
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- Total regioselective and diastereospecific iodolysis of 2,3-epoxyamides promoted by SmI2: Synthesis of (2R*,3R*)- or (2R*,3S*)-2-hydroxy-3-iodoamides
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The use of samarium diiodide as a source of iodides is reported. Thus, 2-hydroxy-3-iodoamides were obtained, with total regioselectivity, by treatment of 2,3-epoxyamides, in which the oxirane ring is 2,3-disubstituted or 2,2,3-trisubstituted, with SmI2. The ring-opening reaction was diastereospecific and (2R*,3R*)- or (2R*,3S*)-2-hydroxy- 3-iodoamides were obtained from cis- or trans-epoxyamides, respectively. The relative configuration of 2-hydroxy-3-iodoamides was established by X-ray analysis. A mechanism to explain this transformation has been proposed. The starting compounds 1 are easily prepared by the reaction of enolates derived from 2-chloroamides with aldehydes at -78°C.
- Concellon, Jose M.,Bardales, Eva,Concellon, Carmen,Garcia-Granda, Santiago,Diaz, M. Rosario
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p. 6923 - 6926
(2007/10/03)
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- A general method for the synthesis of N,N-dialkylaminobutylamines
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A general method for the synthesis of N,N-dialkylaminobutylamines 4 from readily available chloroacetamides 6 is described.
- Seguin, Helene,Gardette, Daniel,Moreau, Marie-France,Madelmont, Jean-Claude,Gramain, Jean-Claude
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p. 4257 - 4272
(2007/10/03)
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- Synthesis, characterisation and X-ray diffraction studies of new lower rim calix[4]arene derivatives containing mixed donor atoms
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New lower rim p-tert-butylcalix[4]arene derivatives containing tetrathiophene functional groups as well as derivatives with two different pendant arms alternately arranged, one of which is in all cases a methyl-sulfanyl substituent whilst the other is either a tertiary amine (aliphatic of alicyclic) or a methylthiophene or an amide substituent, have been synthesised and characterised by 1H and 13C NMR spectroscopy in chloroform at 298 K. The use of phase transfer catalysis in the synthesis of calixarene derivatives is discussed. X-Ray diffraction studies of 5,11,17,23-tetrakis-(1,1-dimethylethyl)-25,26,27,28-tetrakis-[2-(thienyl) methoxy]calix[4]arene 1a and 5,11,17,23-tetrakis-(1,1-dimethylethyl)-25,27-bis[(2-methylsulfanyl)ethoxy]-26, 28-bis[2-(diethylamino)ethoxy]calix[4]arene 2b are reported.
- Danil De Namor, Angela F.,Hutcherson, Robert G.,Sueros Velarde, Felix J.,Alvarez-Larena, Angel,Brianso, Jose L.
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p. 2933 - 2938
(2007/10/03)
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- BENZOTHIAZEPINE AND BENZOXAZEPINE DERIVATIVES AS CHOLECYSTOKININ RECEPTOR ANTAGONISTS
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The present invention relates to novel substituted benzothiazepines and benzoxazepines of the formula STR1 wherein R 1, R 2, R. sup. 7, R 8, R 9 and X are as defined below, and to novel intermediates used in the synthesis of such compounds. Such compounds are useful in the treatment and prevention of gastrointestinal disorders, pain and anxiety disorders.
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- Heterocyclic diamides and method for improving feed utilization and lactation in ruminant animals
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Novel diamides having a nitrogen-containing heterocyclic moiety such as pyridyl are disclosed that are useful for improving feed utilization efficiency of ruminants and for improving lactation of lactating ruminants.
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- Evaluation of glycolamide esters and various other esters of aspirin as true aspirin prodrugs
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A series of glycolamide, glycolate, (acyloxy)methyl, alkyl, and aryl esters of acetylsalicylic acid (aspirin) were synthesized and evaluated as potential prodrug forms of aspirin. N,N-Disubstituted glycolamide esters were found to be rapidly hydrolized in human plasma, resulting in the formation of aspirin as well as the corresponding salicylate esters. These in turn hydrolyzed rapidly to salicylic acid. The largest amount of aspirin formed from the esters were 50 and 55% in case of the N,N-dimethyl- and N,N-diethylglycolamide esters, respectively. Similar results were obtained in blood with the N,N-dimethyl- and N,N-diethylglycolamide esters. Unsubstituted and monosubstituted glycolamide esters as well as most other esters previously suggested to be aspirin prodrugs were shown to hydrolyze exclusively to the corresponding salicylic acid esters. Lipophilicity parameters and water solubilities of the esters were determined, and structural factors favoring ester prodrug hydrolysis at the expense of deacetylation to yield salicylate ester are discussed. The properties of some N,N-disubstituted glycolamide esters of aspirin are highlighted with respect to their use as potential aspirin prodrugs.
- Nielsen,Bundgaard
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p. 727 - 734
(2007/10/02)
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